Filarial nematodes are arthropod-transmitted parasites of vertebrates including humans. Infection is long-term with individual worms surviving for in excess of five years. The consensus of opinion amongst workers in this field is that such longevity reflects modulation of the host immune system such that there is a bias in the production of cytokines indicated by reduced production of the pro-inflammatory IFN-γ and increased production of the anti-inflammatory IL-10. There is also a tendency for regulatory components such as regulatory T cells to be present. Overall, the picture is of an immune response demonstrating a somewhat suppressed, anti-inflammatory phenotype, which is often classified as “modified TH-2” (“TH” is derived from a category of T-lymphocyte referred to as “helper”). It has been speculated that such a phenotype is conducive both to parasite survival and host health, the latter by limiting pathology resulting from an over-aggressive immune response. Consistent with this, it is noteworthy that the majority of humans who harbour these parasites demonstrate little evidence of detrimental pathology.
Modulation of the host immune system is likely to involve the active participation of filarial nematodes and hence considerable effort has been spent in characterising the biological properties of molecules secreted by the worms. Goodridge et al. in the Journal of Immunology, 2001, 167: 940-945 and Journal of Immunology, 2005, 174: 284-93 and Whelan et al. in the Journal of Immunology, 2000, 164: 6453-6460, discuss modulation of macrophage and dendritic cell-derived cytokine production by ES-62 resulting in suppression of the production of pro-inflammatory cytokines which may contribute to the immunomodulatory properties of ES-62 that drive the generation of immune responses with an anti-inflammatory and/or TH-2 phenotype. Although these articles provides a rationale for the changes seen in the immune response, no guidance is provided on whether ES-62 may be useful in the clinic for preventing or treating any particular disease(s), in particular those diseases involving inflammation.
Harnett and Harnett in Biochemica et Biophysica Acta, 2001, 1539: 7-15 report investigations into the underlying mechanism of action of ES-62 and it's component, phosphorylcholine (PC). It is concluded that PC has various actions, including a number of immunomodulatory properties similar to those of ES-62. The mechanisms underlying the immunomodulation have not been defined but it has been demonstrated that ES-62 and PC-conjugated proteins mediate their anti-inflammatory actions on macrophages and dendritic cells via the toll-like receptor (TLR), TLR 4 (Goodridge et al. Journal of Immunology, 2005, 174: 284-93 and Goodridge et al. Parasite Immunology, 2007, 29: 127-37). TLR 4, by sensing bacterial lipopolysaccharide (LPS; also known as endotoxin) is a receptor that signals to the immune system that a pathogenic infection is present and that a pro-inflammatory immune response should be mounted. Similarly, related receptors such as TLR2 and TLR9 sense other pathogen products such as bacterial lipopeptide and CpG DNA motifs, respectively, to trigger pro-inflammatory responses. ES-62 and PC-protein conjugates can suppress pro-inflammatory cytokine (IL-6, IL-12 and TNFα) release from macrophages and dendritic cells driven by TLR2, -4 and -9 targeted pathogen products, presumably by subverting their normal pro-inflammatory function.
Collectively, these findings suggested that ES-62 has potential in the mediation of diseases involving an inflammatory response due to the effect of ES-62 on production of inflammatory cytokines. Consistent with this, ES-62 was found to exhibit protective effects in mouse models of rheumatoid arthritis (collagen-induced arthritis; CIA) and asthma (ovalbumin-induced airway hyperresponsiveness) (McInnes et al. 2003 Journal of Immunology 2003 171:2127-33; Melendez et al. Nature Medicine 2007 13:1375-81). International patent application, publication number WO03024474, describes the clinical use of ES-62 in the treatment of diseases associated with inflammation, such as arthritis. However, in view of the fact that ES-62 is an immunogenic protein and in addition its active moiety results from a helminth-specific post-translational modification, it is not itself appropriate for pharmaceutical application. Thus, since PC, when conjugated to an irrelevant protein such as bovine serum albumin or ovalbumin can mimic the protective effects of ES-62 in CIA (Harnett et al. Ann Rheum Dis 2008 67: 518-23) small molecular compounds having the desired activity are sought, such as non-peptidic small chemical entities based around the structure of the active PC moiety.
The present invention seeks to obviate and/or mitigate the problems seen in the prior art.
In particular, the present invention seeks to provide non-peptide molecules, useful in the treatment of diseases and/or conditions associated with inflammation, such as arthritis, systemic lupus erythematosus, type 1 diabetes, autoimmune hepatitis, psoriasis, inflammatory bowel disease and Crohn's disease, multiple sclerosis, asthma, chronic pulmonary airways disease, in the immune and chemotherapeutic treatment of cancer, in modifying inflammation for the treatment of burns and sepsis, and for use in modifying inflammation in cases of multi-organ failure.